This invention relates to new methods of treating inflammatory diseases. More particularly, the present invention relates to new substituted biphenyl derivatives which are useful in the treatment of asthma, as well as other types of allergic and inflammatory diseases.
Asthmatic attacks are characterized by the narrowing of both large and small airways brought upon by bronchial smooth muscle spasms, edema and inflammation of the bronchial mucose, and production of tenacious mucus. The exact mechanisms involved in asthmatic bronchoconstriction are not completely understood, but an imbalance between beta adrenergic and cholinergic control of the airways has been indicated. Such imbalances appear to be controlled by the cyclic 3',5'-adenosine monophosphate (cyclic AMP or cAMP)-cyclic 3',5'-guanosine monophosphate (cyclic GMP or cGMP) systems with various tissues, such as smooth muscle, mast cells and mucus secreting cells.
Several classes of drugs have been shown useful in the treatment of bronchial asthma. They include the beta adrenergic agents which cause bronchial smooth muscle relaxation and modulate inhibition of mediator release. Among these agents are epinephrine, isoproterenol, ephedrine and beta.sub.2 -adrenergic agents such as metaproterenol, terbutaline, isoetharine, albuterol, bitolterol and fenoterol (5-[1-Hydroxy-2-[[2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl-1,3-benzen ediol).
Corticosteroids, such as prednisone, have been useful in treating asthma as they inhibit attraction of polymorphonuclear leukocytes to the sites of allergic reactions, stimulate synthesis of beta.sub.2 receptors and block leukotriene synthesis. Theophylline, a methyxanthine, has also been used for its ability to relax bronchial smooth muscle and modulate mediator release. Anticholinergic agents, such as atropine and its derivative ipratopium bromide, have been used to block cholinergic pathways that cause airway obstruction.
Used for maintenance therapy alone, cromolyn sodium (disodium cromoglycate) appears to inhibit mediator release and reduce airway hyperactivity.
In recent work, asthma has been recognized as being mediated by an inflammatory response in the respiratory tract [DeMonchy, J., Am. Rev. Resp. Dis. 131:373-376 (1985)]. Recent findings suggest that human T-lymphocytes play a major role in regulating the airway inflammation associated with allergic asthma [Frew, A. J., J. Allergy Clin. Immunol. 85: 533-539 (1990)] and chronic obstructive pulmonary disease [O'Connor, G. T., Am. Rev. Resp. Dis. 140:225-252 (1989)].
In addition to the infiltration of other inflammatory cells into the pulmonary system, human asthmatics and atopics who are dual responders (i.e., show both early and late phase reactions) show a small but significant infiltration of T-lymphocytes following antigen challenge [Frew, A. J. and Kay, A. B., J. Immunol. 141:4158-4164 (1988)]. More importantly, these recruited T-lymphocytes are almost entirely of the CD4.sup.+ (T-helper) type, and there appears to be a direct correlation between the influx of CD4.sup.+ cells, the influx of eosinophils, and the IgE-related allergic response in these individuals [Frew, A. J. and Kay, A. B., J. Immunol. 141:4158-4164 (1988)]. In severe asthmatics, these CD4.sup.+ cells appear to be activated [Corrigan, C. J. and Kay, A. B., Am. Rev. Resp. Dis. 141:970-977 (1990)] by virtue of the increase in IL-2 receptor positive cells. Thus, these cells are capable of producing cytokines (such as IL-3, IL-5, and granulocyte macrophage colony stimulating factor) which can directly affect the differentiation, maturation and activation state of the eosinophils and other inflammatory cells.
Rapamycin, a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus [U.S. Pat. No. 3,929,992] has been shown to prevent the formation of humoral (IgE-like) antibodies in response to an albumin allergic challenge [Martel, R., Can. J. Physiol. Pharm. 55:48 (1977)], inhibit murine T-cell activation [Strauch, M., FASEB 3:3411 (1989)].